A.J. van Wijnen (André)http://repub.eur.nl/ppl/2365/
List of Publicationsenhttp://repub.eur.nl/eur_signature.pnghttp://repub.eur.nl/
RePub, Erasmus University RepositoryMicroRNA functions in osteogenesis and dysfunctions in osteoporosishttp://repub.eur.nl/pub/63902/
Sat, 01 Jun 2013 00:00:01 GMT<div>A.J. van Wijnen</div><div>J. van de Peppel</div><div>J.P.T.M. van Leeuwen</div><div>J.B. Lian</div><div>G.S. Stein</div><div>J.J. Westendorf</div><div>M.-J. Oursler</div><div>K.M. Im</div><div>H. Taipaleenmäki</div><div>E. Hesse</div><div>S. Riester</div><div>S. Kakar</div>
MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression that control osteoblast mediated bone formation and osteoclast-related bone remodeling. Deregulation of miRNA mediated mechanisms is emerging as an important pathological factor in bone degeneration (eg, osteoporosis) and other bone-related diseases. MiRNAs are intriguing regulatory molecules that are networked with cell signaling pathways and intricate transcriptional programs through ingenuous circuits with remarkably simple logic. This overview examines key principles by which miRNAs control differentiation of osteoblasts as they evolve from mesenchymal stromal cells during osteogenesis, or of osteoclasts as they originate from monocytic precursors in the hematopoietic lineage during osteoclastogenesis. Of particular note are miRNAs that are temporally upregulated during osteoblastogenesis (eg, miR-218) or osteoclastogenesis (eg, miR-148a). Each miRNA stimulates differentiation by suppressing inhibitory signaling pathways ('double-negative' regulation). The excitement surrounding miRNAs in bone biology stems from the prominent effects that individual miRNAs can have on biological transitions during differentiation of skeletal cells and correlations of miRNA dysfunction with bone diseases. MiRNAs have significant clinical potential which is reflected by their versatility as disease-specific biomarkers and their promise as therapeutic agents to ameliorate or reverse bone tissue degeneration.A central dinucleotide within vitamin D response elements modulates DNA binding and transactivation by the vitamin D receptor in cellular response to natural and synthetic ligands.http://repub.eur.nl/pub/13017/
Fri, 26 Apr 2002 00:00:01 GMT<div>G.J.C.M. van den Bemd</div><div>M. Jhamai</div><div>A. Staal</div><div>A.J. van Wijnen</div><div>J.B. Lian</div><div>G.S. Stein</div><div>H.A.P. Pols</div><div>J.P.T.M. van Leeuwen</div>
There is considerable divergence in the sequences of steroid receptor
response elements, including the vitamin D response elements (VDREs). Two
major VDRE-containing and thus 1,25-dihydroxyvitamin D(3)
(1,25-(OH)(2)D(3))-regulated genes are the two non-collagenous,
osteoblast-derived bone matrix proteins osteocalcin and osteopontin. We
observed a stronger induction of osteopontin than osteocalcin mRNA
expression by 1,25-(OH)(2)D(3). Subsequently, we have shown that vitamin D
receptor/retinoid X receptor alpha (VDR/RXRalpha) heterodimers bind more
tightly to the osteopontin VDRE than to the osteocalcin VDRE. Studies
using point mutants revealed that the internal dinucleotide at positions 3
and 4 of the proximal steroid half-element are most important for
modulating the strength of receptor binding. In addition, studies with
VDRE-driven luciferase reporter gene constructs revealed that the central
dinucleotide influences the transactivation potential of VDR/RXRalpha with
the same order of magnitude as that observed in the DNA binding studies.
The synthetic vitamin D analog KH1060 is a more potent stimulator of
transcription and inducer of VDRE binding of VDR/RXR in the presence of
nuclear factors isolated from ROS 17/2.8 osteoblast-like cells than the
natural ligand 1,25-(OH)(2)D(3). Interestingly, however, KH1060 is
comparable or even less potent than 1,25-(OH)(2)D(3) in stimulating VDRE
binding of in vitro synthesized VDR/RXRalpha. Thus, the extent of
1,25-(OH)(2)D(3)- and KH1060-dependent binding of VDR/RXRalpha is
specified by a central dinucleotide in the VDRE, and the ligand-induced
effects on DNA binding are in part controlled by the cellular context of
nuclear proteins.Antagonistic effects of transforming growth factor-beta on vitamin D3 enhancement of osteocalcin and osteopontin transcription: reduced interactions of vitamin D receptor/retinoid X receptor complexes with vitamin E response elementshttp://repub.eur.nl/pub/8608/
Mon, 01 Jan 1996 00:00:01 GMT<div>A. Staal</div><div>J.B. Lian</div><div>A.J. van Wijnen</div><div>R.K. Desai</div><div>H.A.P. Pols</div><div>J.C. Birkenhäger</div><div>H.F. Deluca</div><div>D.T. Denhardt</div><div>J.L. Stein</div><div>G.S. Stein</div><div>J.P.T.M. van Leeuwen</div>
Osteocalcin and osteopontin are noncollagenous proteins secreted by
osteoblasts and regulated by a complex interplay of systemic and locally
produced factors, including growth factors and steroid hormones. We
investigated the mechanism by which transforming growth factor-beta (TGF
beta) inhibits 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-enhanced expression
of the osteocalcin (OC) and osteopontin (OP) genes. ROS 17/2.8 cells, in
which both genes are expressed, were transfected with reporter constructs
driven by native (i.e. wild-type) rat OC and mouse OP promoters. TGF beta
abrogated the 1,25-(OH)2D3 enhanced transcription of both the OC and OP
genes. The inhibitory TGF beta response for each requires vitamin D
response element (VDRE) sequences, although there are additional
contributions from proximal basal regulatory elements. These
transcriptional effects were further investigated for contribution of the
trans-activating factors, which interact with OC and OP VDREs, involving
the vitamin D receptor (VDR) and retinoid X receptor (RXR). Gel mobility
shift assays show that TGF beta significantly reduces induction of the
heterodimers VDR/RXR complexes in 1,25-(OH)2D3-treated ROS 17/2.8 cells.
However, Western blot and ligand binding analysis reveal that TGF beta
does not affect nuclear availability of the VDR. We also show that
activator protein-1 activity is up-regulated by TGF beta; thus, activator
protein-1 binding sites in the OC promoter may potentially contribute to
inhibitory effects of TGF beta on basal transcription. Our studies
demonstrate that the inhibitory action of TGF beta on the 1,25-(OH)2D3
enhancement of OC and OP transcription in osteoblastic cells results from
modulations of protein-DNA interactions at the OC and OP VDRE, which
cannot be accounted for by changes in VDR protein levels. As OC and OP
participate in bone turnover, our results provide insight into the
contributions of TGF beta and 1,25-(OH)2D3 to VDR-mediated gene regulatory
mechanism operative in bone formation and/or resorption events.